Preparation and characterization of nanocrystals for solubility and dissolution rate enhancement of nifedipine.

Disclosed is a rapidly disintegrating solid oral dosage form of a poorly soluble active ingredient and at least one pharmaceutically acceptable water-soluble or water dispersible excipient, wherein the poorly soluble active ingredient particles have an average diameter, prior to inclusion in the dosage form, of less than about 2000 nm. The dosage form of the invention has the advantage of combining rapid presentation and rapid dissolution of the active ingredient in the oral cavity.

Rapidly disintegrating solid oral dosage form

Review of Disintegrants and the Disintegration Phenomena.

The utility of hypromellose acetate succinate (HPMCAS), a cellulosic enteric coating agent, as a carrier in a solid dispersion of nifedipine (NP) was evaluated in comparison with other polymers, including hypromellose (HPMC), hypromellose phthalate (HPMCP), methacrylic acid ethyl acrylate copolymer (MAEA), and povidone (PVP). An X-ray diffraction study showed that the minimum amount of HPMCAS required to make the drug completely amorphous was the same as that of other cellulosic polymers, and less than that in dispersions using non-cellulosic polymers. Hypromellose acetate succinate showed the highest drug dissolution level from its solid dispersion in a dissolution study using a buffer of pH 6.8. This characteristic was unchanged after a storage test at high temperature and high humidity. The inhibitory effect of HPMCAS on recrystallization of NP from a supersaturated solution was the greatest among all the polymers examined. Further, the drug release pattern could be modulated by altering the ratio of succinoyl and acetyl moieties in the polymer chain. Our results indicate that HPMCAS is an attractive candidate for use as a carrier in solid dispersions.

Evaluation of hypromellose acetate succinate (HPMCAS) as a carrier in solid dispersions.

The purpose of this research was to mask the intensely bitter taste of ondansetron HCl and to formulate a rapiddisintegrating tablet (RDT) of the taste-maske drug. Taste masking was done by complexing ondansetron HCl with aminoalkyl methacrylate copolymer (Eudragit EPO) in different ratios by the precipitation method. Drug-polymer complexes (DPCs) were tested for drug content, in vitro taste in simulated salivary fluid (SSF) of pH 6.2, and molecular property. Complex that did not release drug in SSF was considered taste-masked and selected for formulation RDTs. The complex with drug-polymer ratio of 8∶2 did not show drug release in SSF; therefore, it was selected. The properties of tablets such as tensile strength, wetting time, water absorption ratio, in vitro disintegration time, and disintegration in the oral cavity were investigated to elucidate the wetting and disintegration characteristics of tablets. Polyplasdone XL-10 7% wt/wt gave the minimum disintegration time. Tablets of batch F4 containing spray-dried mannitol and microcrystalline cellulose in the ratio 1∶1 and 7% wt/wt Polyplasdone XL-10 showed faster disintegration, within 12.5 seconds, than the marketed tablet (112 seconds). Good correlation between in vitro disintegration behavior and in the oral cavity was recognized. Taste evaluation of RDT in human volunteers revealed considerable taste masking with the degree of bitterness below threshold value (0.5) ultimately reaching to 0 within 15 minutes, whereas ondansetron HCl was rated intensely bitter with a score of 3 for 10 minutes. Tablets of batch F4 also revealed rapid drug release (t90, 60 seconds) in SGF compared with marketed formulation (t90, 240 seconds;P<.01). Thus, results conclusively demonstrated successful masking of taste and rapid disintegration of the formulated tablets in the oral cavity.

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Taste masking of ondansetron hydrochloride by polymer carrier system and formulation of rapid-disintegrating tablets.

We attempted the development of rapid oral disintegration tablets by direct compression using co-ground mixture of D-mannitol and crospovidone. The co-ground mixture was prepared with a vibration rod mill. The tablets were formed by compression using a single punch-tableting machine after addition of the co-ground mixture to non-ground D-mannitol, crospovidone and magnesium stearate. Regarding the properties of tablets, hardness and the time of disintegration were measured. The particle diameter and specific surface area of the co-ground mixture were measured. The tablets manufactured from a physical mixture of 30% (w/w) co-ground mixture of D-mannitol and crospovidone (mixed ratio 9 :1) with 65.5% (w/w) of non-ground mannitol, 4% (w/w) of crospovidone, and 0.5% (w/w) of magnesium stearate had good properties for rapidly disintegrating tablets in the oral cavity. They showed the hardness of 4.9 kg and disintegration time of 33 s. We found that adding co-ground mixture of D-mannitol and crospovidone is useful in enhancing hardness of the tablets that could not be achieved by addition of their individually ground mixture. The improvement in the hardness of the tablets was also observed when other saccharides and disintegrants were used. This method was proved to be applicable in the manufacture of tables of ascorbic acid, a water-soluble drug and nifedipine, a slightly water soluble drug; and the dissolution rate of nifedipine from the tablets in water was remarkably improved. The particle sizes of D-mannitol in the co-ground mixture were smaller than that of the individually ground mixture, resulting in a larger specific surface area of the co-ground mixture than that of the individually ground mixture. Therefore, it was presumed that crospovidone acted as a grinding assistant for D-mannitol in the co-grinding process, enhancing the hardness of tablets by increasing the contact area among powder particles.

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Studies of rapidly disintegrating tablets in the oral cavity using co-ground mixtures of mannitol with crospovidone.

Nifedipine is a poorly water soluble drug that demonstrates low bioavailability. In a previous study, a coground mixture of nifedipine with sodium deoxycholate (DCNa), a bile salt, immediately produced colloidal particles when dispersed in water. In this study, the effect of the weight fraction of DCNa, grinding time, dissolution media, and storage conditions on colloidal particle formation in solution was investigated. The coground mixture was prepared with a vibration rod mill, and its solid state was characterized using powder X-ray diffraction. A laser diffraction particle size analyzer was used to determine the particle size distribution curve in water. The size of particles formed in solution decreased with an increase in the weight fraction of DCNa and grinding time. A nifedipine-DCNa (1 : 2 w/w) mixture coground for 30 min was used in the experiments. Colloidal particle formation from the coground mixture was also observed in dissolution media of water and a pH 6.8 buffer solution at 37°C. Most pr...

A nifedipine coground mixture with sodium deoxycholate. II. Dissolution characteristics and stability

Sodium deoxycholate (DCNa) is a bile salt that forms multimolecular inclusion compounds with a variety of organic substances. In this study, complex formulation of DCNa with nifedipine, a poorly water soluble drug, by grinding was investigated. The coground mixture was prepared with a vibration rod mill, and its solid state was characterized using powder X-ray diffraction, differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR) spectroscopy. A laser diffraction particle size analyzer was also used to determine the particle size distribution curve in solution. When a nifedipine-DCNa (1:2 w/w) mixture coground for 30 min was dispersed into water and a pH 6.8 buffer solution, a semitransparent colloidal solution occurred immediately; 90% of the total particles formed in solution had a diameter less than 600 nm. Both powder X-ray diffraction peaks and DSC endothermic peak of nifedipine crystals were not found for the coground mixture, whereas a new exothermic peak was observed on DSC th...

A Nifedipine Coground Mixture with Sodium Deoxycholate. I. Colloidal Particle Formation and Solid-State Analysis

PROBLEM TO BE SOLVED: To provide an intraorally rapid disintegration tablet that has a suitable hardness and rapid disintegration in the oral cavity and a method for manufacturing the same. SOLUTION: The objective intraorally rapid disintegration tablet comprises a co-crushed mixture of a saccharide and a disintegrator, and preferably further a tableting mixture of an uncrushed saccharide and a disintegrator. Then, the mixture is compression-molded by the direct tableting method (the tableting process) to give the objective intraoral rapid disintegration tablet.

Kenji Hironaka

Papers

Studies of rapidly disintegrating tablets in the oral cavity using co-ground mixtures of mannitol with crospovidone.

A nifedipine coground mixture with sodium deoxycholate. II. Dissolution characteristics and stability

A Nifedipine Coground Mixture with Sodium Deoxycholate. I. Colloidal Particle Formation and Solid-State Analysis

Intraorally rapid disintegration tablet and method for producing the same